Gene-by-Gene Interactions and Lung Fluid Balance in Patients with Heart Failure

心力衰竭患者的基因间相互作用和肺液平衡

• 批准号: 8158652
• 负责人: ERIC M SNYDER
• 金额: $ 40.04万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8158652
• 关键词: ADRB2 gene; Admission activity; Adrenergic Agents; Adrenergic Receptor; Agonist; Alternative Therapies; Alveolar; Alveolar Cell; Award; Breathing; Cessation of life; Characteristics; Clinical; Clinical Research; Code; Development; Disease; Elderly; Epinephrine; Equilibrium; Excision; Floods; Fluid Balance; Future; Genes; Genetic; Genetic Variation; Goals; Heart failure; Homeostasis; Hospitals; Human; Individual; Ions; Knowledge; Laboratories; Liquid substance; Lung; Mediating; Methods; Mission; Norepinephrine; Outcome; Patients; Persons; Phenylethanolamine N-Methyltransferase; Population; Predisposition; Proteins; Public Health; Pulmonary Edema; Regulation; Research; Risk; Symptoms; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Translating; United States; United States National Institutes of Health; Variant; Water; adrenergic; apical membrane; base; clinical application; clinical practice; epithelial Na+ channel; gene interaction; gene therapy; improved; innovation; response

DESCRIPTION (provided by applicant): Decompensated heart failure challenges the ability of the lungs to maintain fluid homeostasis and can result in alveolar flooding and death; however, not all patients with decompensated heart failure develop pulmonary edema, despite similar clinical characteristics, suggesting a genetic influence on susceptibility to pulmonary edema in this population. In the lungs, alveolar Na+ and fluid clearance are primarily regulated by the activity of epithelial Na+ channels (ENaC). The activity and number of ENaCs are regulated by ¿2 adrenergic receptors (ADRB2s). Stimulation of the ADRB2s by an endogenous (epinephrine) or exogenous agonist increases alveolar fluid clearance. Therefore, there are three key proteins involved in alveolar fluid clearance: ADRB2s, ENaCs, and epinephrine. There are common functional variants in the genes that encode the ADRB2, the alpha subunit of the ENaC, and phenylethanolamine N- methyltransferase (PNMT, which converts norepinephrine to epinephrine). It remains unclear what effects of these genes will be on patients with heart failure. Our long term goal is to determine appropriate therapeutic interventions for improving ion and lung fluid regulation in disease based on genetic information. The objective in this proposal is to determine the influence of genetic variation on lung Na+ and fluid handling, which is likely to have significant clinical applications, particularly in patients with heart failure who have an elevated adrenergic drive. Our central hypothesis is that genetic variation of the ADRB2, ENaC, and PNMT will influence baseline lung fluid and lung fluid clearance in response to a ¿-agonist. The rationale for the proposed research is that determining how these genes regulate lung fluid in heart failure will allow for personalization of current therapy as well as utilization of alternative therapies to reduce the susceptibility of pulmonary edema in heart failure. This proposal is significant because we will explore the therapeutic effects of stimulation of the ¿2-adrenergic receptors on lung fluid balance, and how genetic variation can influence this therapeutic response. This will add to the understanding of specific therapies used to reduce the risk of pulmonary edema in patients with HF. The research proposed is innovative because we will be testing the influence of genetic variation of ADRB2, ENaC and PNMT (which have not been explored together in patients with HF) on lung ion and fluid regulation in HF, we are determining how multiple genes interact together to influence lung fluid balance in patients with HF, and, finally, we have recently developed a new technique to assess lung ion and fluid changes which we will couple with existing methods to expand techniques that can be used to assess changes in lung water. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because complications from heart failure (HF), including symptoms of pulmonary edema, are the number one reason for hospital admissions in the United States. Understanding the genetic influence to this susceptibility is key for therapeutic progress in HF. Thus, the proposed research is relevant to the NIH mission in that it will translate clinical research obtained in a laboratory setting in HF patients to clinical practice.

描述(申请人提供)：失代偿性心力衰竭挑战肺维持液体动态平衡的能力，可导致肺泡积水和死亡；然而，尽管临床特征相似，但并不是所有失代偿性心力衰竭患者都会发生肺水肿，这表明在这一人群中对肺水肿的易感性存在遗传影响。在肺中，肺泡Na+和液体清除主要受上皮性Na+通道(ENaC)活动的调节。ENaCs的活性和数量受肾上腺素能受体(ADRB2)的调节。内源性(肾上腺素)或外源性激动剂刺激ADRB2可增加肺泡液清除。因此，有三种关键蛋白参与肺泡液清除：ADRB2、ENaCs和肾上腺素。在编码ADRB2和苯乙醇胺N-甲基转移酶(PNMT，将去甲肾上腺素转化为肾上腺素)的基因中有常见的功能变异。ADRB2是ENaC的阿尔法亚基。目前尚不清楚这些基因将对心力衰竭患者产生什么影响。我们的长期目标是根据遗传信息确定适当的治疗干预措施，以改善疾病中的离子和肺液调节。这项建议的目的是确定遗传变异对肺Na+和液体处理的影响，这可能具有重要的临床应用，特别是在肾上腺素能驱动力升高的心力衰竭患者中。我们的中心假设是ADRB2、ENaC和PNMT的遗传变异会影响基础肺液和肺液清除对激动剂的反应。这项拟议研究的基本原理是，确定这些基因如何调节心力衰竭中的肺液，将允许个性化目前的治疗以及利用替代疗法来降低心力衰竭中肺水肿的易感性。这一建议意义重大，因为我们将探索刺激2-肾上腺素能受体对肺液平衡的治疗效果，以及遗传变异如何影响这种治疗反应。这将增加对用于降低心力衰竭患者肺水肿风险的特定治疗方法的理解。提出的这项研究是创新的，因为我们将测试ADRB2、ENaC和PNMT(尚未在HF患者中一起探索)基因变异对HF患者肺离子和液体调节的影响，我们正在确定多个基因如何相互作用影响HF患者的肺液平衡，最后，我们最近开发了一种评估肺离子和液体变化的新技术，我们将与现有方法相结合，扩展可用于评估肺水变化的技术。 公共卫生相关性：这项拟议的研究与公共健康相关，因为心力衰竭(HF)的并发症，包括肺水肿症状，是美国住院的首要原因。了解遗传因素对这种易感性的影响是心力衰竭治疗进展的关键。因此，这项拟议的研究与美国国立卫生研究院的任务相关，因为它将把在实验室环境中获得的心衰患者的临床研究转化为临床实践。